Microbial infections are responsible for both global pandemics and local epidemics, and may result in serious mortalities if left untreated or appropriate treatment is not provided. Importantly, many available antibiotics are increasingly ineffective due to acquisition of resistance by many microbes. Exemplary multiresistant bacterial pathogens include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extended spectrum ß-lactamase formers (ESBL), carbapenem-resistant Enterobacteriaceae (CRE), multiresistant Pseudomonas and Acinetobacter species. For these bacteria, only a few of the existing antibiotics are therapeutically effective.
There is a need for novel antibiotic compounds. There is also a need for novel and effective treatments for bacterial infections and a variety of disease states for which bacterial infections are implicated.
We reported in WO2013045600 the discovery of a novel class of antibiotics that we first called the Odilomycins, and that we then renamed the Odilorhabdins. The 3 first odilorhabdin molecules are naturally produced by the bacteria Xenorhabdus nematophila. Odilorhabdins have interesting antibacterial activities against bacterial pathogens, including against multidrug-resistant clinical isolates. However, a drawback of the original Odilorhabdins is their affinity to calcium channels (type N) conferring them significant adverse events. These adverse events preclude the direct use of the natural Odilorhabdins as drugs. We succeeded to overcome this issue by designing much safer synthetic analogs of the Odilorhabdins that retain antibacterial activity, following a medicinal chemistry program and structure-activity relationships studies. These safer antibacterial analogs are the purpose of this patent application.